Lipocalin-2, a mitokine that mediates white to brown fat crosstalk

项目摘要/摘要 三分之一的美国成年人患有肥胖症。肥胖症对 许多其他威胁生命的疾病的流行，如2型糖尿病， 心血管疾病、癌症等。尽管已经投入了大量资源 为解决这一重大公共卫生威胁而投入的资金，事实是，目前仅限于 已经开发出治疗肥胖症的药物治疗方法。一个In- 迫切需要深入了解肥胖的原因，以促进发现 更有效的治疗方法。人类的脂肪组织有两种：白色和白色 棕色脂肪组织。它们具有不同的形态，并执行不同的功能。 白色脂肪以类脂的形式储存过多的能量，而棕色脂肪则消耗 通过适应性生热作用(即产生热量)产生过多的能量。一种常见的 人类肥胖现象是棕色脂肪转化为白色脂肪的一个过程 被鉴定为美白。逆转棕色脂肪美白，激活棕色脂肪功能， 起到减肥的作用。这项研究的首要目标是调查 Lipocalin 2(LCN-2)，一种潜在的促进棕色脂肪美白的因素。申请人 最近对他的脂肪细胞线粒体功能障碍进行了一系列筛查 模特。LCN-2被认为是导致白色向棕色转化的主导因素 脂肪组织串扰，诱导棕色脂肪变白。因此，这项建议被提出 为了评估中心假设：LCN-2，一种来自白色脂肪的分泌因子，是 由线粒体损伤引起，并促进棕色脂肪美白。在目标1中，单元格 体外培养系统将被用来证明LCN-2在棕色中是必需的。 脂肪美白。在目标2中，将提供来自(活体)小鼠的证据以进一步评估 LCN-2在棕色脂肪美白和代谢后果(即寒冷)中的作用 不容忍和肥胖)。这项研究将通过定义一部小说来填补知识空白 美白因子有助于了解棕色脂肪组织是如何变白的。 此外，这项研究具有翻译价值，因为LCN-2的中和 本身或抑制LCN-2受体具有巨大的改善潜力 布朗反对美白，并反过来寻找减轻肥胖的创新疗法.

Project Summary/Abstract One third of American adults are suffering from obesity. Obesity significantly contributes to the prevalence of numerous other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been invested to resolve this major public health threat, the fact is that, currently, only limited methods of pharmacological therapeutics have been developed to treat obesity. An in- depth understanding of the reasons for obesity is urgently needed to facilitate finding more effective therapeutics. There are two types of fat tissue in humans: white and brown adipose tissue. They have different morphologies and perform distinct functions. While white fat stores excessive energy in the form of lipids, brown fat consumes excessive energy through adaptive thermogenesis (i.e., generating heat). A common phenomenon in human obesity is the conversion of brown fat into white fat, a process identified as whitening. Reversing brown fat whitening activates brown fat function and exerts anti-obesity effects. The overarching goal of this study is to investigate the role of lipocalin 2 (LCN-2), a potential factor that promotes brown fat whitening. The applicant recently performed a series of screenings in his adipocyte mitochondrial dysfunction model. LCN-2 was suggested to be a leading factor that drives the white to brown adipose tissue crosstalk to induce brown fat whitening. Therefore, this proposal is set out to evaluate the central hypotheses: LCN-2, a secreting factor from the white fat, is induced by mitochondrial distress and promotes brown fat whitening. In Aim 1, cell culture systems (in vitro) will be utilized to demonstrate that LCN-2 is required in brown fat whitening. In Aim 2, evidence from mice (in vivo) will be provided to further evaluate the role of LCN-2 in brown fat whitening and metabolic consequences (i.e., cold intolerance and obesity). This study will fill a knowledge gap through defining a novel whitening factor in understanding how the brown adipose tissue becomes whitened. Furthermore, this study has translational merits because either neutralization of LCN-2 per se or inhibition of the LCN-2 receptor holds an enormous potential to ameliorate brown AT whitening and, in turn, to identify innovative therapeutics that alleviate obesity.